Anti-DNA autoantibodies are found in the sera of patients with a variety of autoimmune diseases, including systemic lupus erythematosus. The presence of anti-double stranded DNA autoantibodies is one of the hallmarks of the disease and anti- DNA antibodies are involved in the formation of immune deposits during lupus nephritis. Nevertheless, the mechanisms triggering the production of anti-DNA autoantibodies are not yet understood. Activation by foreign antigens or by anti-idiotypic antibodies are among the hypothesis proposed to explain the emergence of such autoreactive clones. We will test these hypothesis by inducing in normal mice the production of anti-DNA autoantibodies after stimulation with a protein antigen (lysozyme) or anti-idiotypic antibodies against antibodies cross-reacting with lysozyme of DNA. Our approach is based on preliminary results showing possible cross-reactivities between monoclonal anti- lysozyme and anti-DNA antibodies. In a different set of experiments, we will explore the possibility of direct idiotypic interactions between anti-DNA and anti-histone H1 antibodies. The existence of such idiotypic interactions could lead to the formation of pathogenic immune complexes. The monoclonal autoantibodies obtained in our study will be further characterized with respect to their immunochemical properties, pathogenic role and nucleotide sequences.